Obesity is a major health problem in the U.S. However, how adipose tissue disorders cause insulin resistance and related metabolic diseases is not known. Study of single gene disorders of adipose tissue may elucidate the mechanisms involved in these processes. Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder that results in almost complete absence of adipose tissue. Familial partial lipodystrophy, Dunnigan variety (FPLD) is an autosomal dominant disorder characterized by gradual loss of subcutaneous adipose tissue in both the upper and lower extremities during early adolescence, and excessive adipose tissue on the face and neck. Other common features include insulin resistance, diabetes mellitus, hypertriglyceridemia, low levels of high density lipoprotein, acanthosis nigricans and in some women, hirsutism and menstrual abnormalities. The genetic basis and pathophysiology of the metabolic complications in these disorders is not known. The project therefore has two aims: 1) to characterize metabolic abnormalities in patients with CGL and FPLD and 2) to identify the molecular basis of these disorders. To accomplish these aims, we have collected a number of well-characterized pedigrees. We will study body fat distribution by anthropometry and whole body magnetic resonance imaging and will measure insulin sensitivity, plasma lipoproteins, free fatty acids, glycerol and other metabolic variables. We have localized the FPLD gene to chromosome 1q21-22 by genome-wide linkage analysis. Similar studies are underway to localize the gene for CGL. Following chromosomal localization and fine mapping, candidate genes, already mapped or identified by positional cloning into these regions will be examined for mutations using the single strand conformation polymorphism (SSCP), denaturing high performance liquid chromatography (DHPLC) or direct sequencing. The identification of gene defects will allow us to define the normal role of these genes in insulin action and body fat distribution and will lead to a better understanding of how common adipose tissue disorders such as obesity cause insulin resistance and other metabolic complications.